Large study reveals new genetic variants that raise risk for prostate cancer
In an analysis of genetic information among more than 87,000 men, a global team of scientists says it has found 23 new genetic variants – common differences in the genetic code—that increase a man’s risk for prostate cancer. The so-called “meta-analysis,” believed to be the largest of its kind, has revealed once hidden mutations among men in a broad array of ethnic groups comprising men of European, African, Japanese and Latino ancestry.
The meta-analysis combined information from smaller studies, according to William B. Isaacs, Ph.D., a genetic scientist at the Brady Urological Institute at the Johns Hopkins University School of Medicine. “There is a power in numbers that helped us find new variants that were only hinted at in smaller study populations, especially among minority men, and as we found the same variants across several populations, the evidence became stronger that they were definitively linked to prostate cancer,” Isaacs said.
To help build the number of samples for the current study, described online Sept. 14 in Nature Genetics, Isaacs and Alan Partin, M.D., Ph.D., Brady Urological Institute director, contributed blood and tissue samples and data from 800 African-American men (400 with prostate cancer and 400 cancer-free) treated at Johns Hopkins to the study. All told, the samples included information on 43,303 prostate cancer patients and 43,737 men without prostate cancer.
Scientists at the Institute of Cancer Research and Royal Marsden National Health Services Foundation Trust in London, UK, and the University of Southern California led the analysis, which scanned more than 10 million areas of the genome where one genetic building block of DNA was switched for another, referred to as genetic variants, or more specifically, single-nucleotide polymorphisms (SNPs).
The team then compared the scanned genome regions of prostate cancer patients with prostate cancer-free men to find the 23 new SNPs they now link to prostate cancer. Together with 76 previously discovered SNPs, the variants account for one-third of the inherited risk for prostate cancers in men of European descent. Because the variants are inherited commonly among populations, they can appear in men with little or no family history of prostate cancer.
“Inheriting any single one of these genetic variants has only a small effect of prostate cancer risk,” says Partin. “However, a subset of men will inherit many of these variants, putting them at substantially increase risk for the disease, from three to six times the population average. Men with these risk levels may benefit from disease screening at earlier ages.”
Prostate cancer risk factors
Some common risk factors for prostate cancer include:
Race: Studies show that African American men are approximately 60 percent more likely to develop prostate cancer in their lifetime than Caucasian or Hispanic men.
Age: The risk of developing prostate cancer increases with age. While only one in 10,000 men under age 40 will be diagnosed with prostate cancer, one in 15 men in their 60s will be diagnosed with the disease.
Family history: Men with an immediate blood relative, such as a father or brother, who has or had prostate cancer, are twice as likely to develop the disease. If there is another family member diagnosed with the disease, the chances of getting prostate cancer increase.
Diet: A diet high in saturated fat, as well as obesity, increases the risk of prostate cancer.
High testosterone levels: Men who use testosterone therapy are more likely to develop prostate cancer, as an increase in testosterone stimulates the growth of the prostate gland.
Prostatic intraepithelial neoplasia (PIN): This condition may be associated with increased risk of prostate cancer. PIN is a condition in which prostate gland cells look abnormal when examined with a microscope. It is not necessarily linked with any symptoms. Nearly one half of men will be diagnosed with PIN before age 50.
Genome changes: Certain genes have been known to elevate prostate cancer risks, such as BRCA1 and BRCA2 genes.
Isaacs says that men with a family history of prostate cancer are already encouraged to be screened at an earlier age, “but family history may be difficult to pin down.”
He suggests that the identification of prostate cancer-related SNPS could serve as a “molecular family history” to enable better screening guidelines and therapies.
Overweight and obesity
Prostate cancer death risk, and aggressive prostate cancer risk, is 9-15% higher per 5-unit body mass index (BMI) increment, meta-analyses have shown. Localised prostate cancer risk is 4-6% lower per 5-unit BMI increment, meta-analyses have shown. This difference by prostate cancer aggressiveness may reflect difficulty detecting and treating prostate cancer in overweight and obese men.
Prostate cancer risk may be 30% higher in men in Europe with metabolic syndrome (characterised by overweight/obesity, ineffective insulin use, diabetes and hypertension), a meta-analysis showed; this may be mainly linked to hypertension and abdominal obesity.
Isaacs says all 23 SNPs were located in non-protein encoding regions of DNA - genetic material that is not a blueprint for a specific protein product - suggesting that the SNPs may be important in regulating genes rather than making proteins. Some of the newly identified SNPs have been previously linked to cancer.
Isaacs is the William Thomas Gerrard, Mario Anthony Duhon and Jennifer and John Chalsty Professor of Urology and professor of oncology at the Johns Hopkins University School of Medicine, and a member of the Johns Hopkins Brady Urological Institute and Kimmel Cancer Center. Partin is the professor of urology, oncology and pathology at the Johns Hopkins University School of Medicine and the David Hall McConnell Director of Urology and urologist in chief for the Department of Urology and Oncology.
Funding for the study was provided by the U.S. Department of Defense, National Institutes of Health’s National Cancer Institute, Cancer Research UK, Prostate Cancer UK, the EU, as well as Patrick Henry, P. Kevin Jaffe, and The Peter Jay Sharpe Foundation.
Prostate cancer risk is lower in men with the following medical conditions or using the following treatments, meta- and pooled analyses, systematic reviews or cohort studies have shown:
Diabetes - 15-28% lower risk (no variation by diabetes treatment type)
Systemic lupus erythematosus - up to a third lower risk.
Human immunodeficiency virus (HIV) - 30-31% lower risk,114,115 does not appear to be explained by increased PSA testing in HIV-positive men.
Paracetamol (aggressive prostate cancer) - 38% lower risk with 30+ pills per month for 5+ years risk (though may reflect increased likelihood of early-stage diagnosis).
Aspirin - 8-14% lower risk in users versus non-users, stronger effect for longer-term use and for advanced prostate cancer; unclear association between aspirin use and risk of prostate cancer death.
Warfarin - 17-31% lower risk in users versus non-users.
A full list of scientists who contributed to the study can be found at http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.3094.html#acknowledgments.
On the Web:
Nature Genetics: DOI: 10.1038/ng.3094
Johns Hopkins Medicine